Molecular mechanism of antagonist recognition and regulation of the α-adrenoceptor.

The α-adrenoceptor (αAR) is a critically important class of G protein-coupled receptors, comprising 3 subtypes: αAR, αAR, and αAR. Currently, drugs targeting αAR have been used in the treatment of various diseases. Notably, antagonists of αAR play a pivotal role in the management of benign prostatic hyperplasia. In recent years, researchers have developed selective antagonists for the αAR subtype that have a minimal impact on blood pressure for the treatment of benign prostatic hyperplasia. However, these agents still exhibit certain side effects, necessitating the continuous development of new medications to mitigate adverse reactions while achieving more precise regulation. We report the cryo-EM structures of the αAR-selective antagonist doxazosin and the αAR subtype-selective antagonist silodosin in complex with αAR, demonstrating that M292 and V185 are key residues that confer subtype selectivity to silodosin. In addition, modifications to αAR enhanced silodosin's inhibitory efficacy against αAR. These findings deepen our understanding of the recognition patterns of αAR antagonists, revealing the molecular principles underlying the selective binding of silodosin to αAR and promoting further research and development of subtype-selective drugs targeting αAR.